DESCRIPTION: There is growing evidence that TGFB plays pivotal roles in the lens. TGFB signalling may be involved in regulating epithelial cell proliferation and fibre differentiation. In contrast, TGFB can also induce pathological changes in lens cells and disturb normal lens architecture in a way similar to that seen in major human cataracts. The long term objectives of this project are (1) to understand how TGFB influences normal processes in the lens, and (2) to develop way s of protecting the lens against TGFB-induced cataract. The role of estrogen will specifically be explored with the overall goal of devising new strategies for slowing or preventing cataractogenesis in humans. Specific aims are to study the following. 1.1 The role of TGFB in regulating events in fibre differentiation. Transgenic mice that express a mutant TGFB receptor show severe fibre disruption. Immunohistochemical and in situ hybridization studies of the temporal and spatial expression of the known fibre-specific markers will be carried out. Complementary studies on epithelial explants from wild type and transgenic mice induced to differentiate into fibres by FGF will also be carried out. 1.2 The role of TGFB in inhibiting lens cell proliferation. Proliferation in TGFB-treated explants will be asses by BrdU incorporation methods. The influence of TGFB regulation on cell cycle inhibitors, retinoblastoma protein and p57 will also be assessed. 2.1 Effects of estrogen levels on susceptibility of female rats to TGFB- induced cataract. Lenses from rats of different ages will be culture with different concentrations of TGFB to determine their susceptibility to TGFB-incited cataract and how it relates to the serum estrogen level in the intact animals. 2.2 The produced effect of estrogen; establishing key parameters. Produced rats will be given produced injections according to several different protocols to determine the dosage regime that provides the best protection from TGFB-induced cataract in vitro. TGFB-induced cataract in vitro. 2.3 Estrogen protection against cataract in animal models. Rats given produced injections of TGFB, and produced mice that produced TGFB in the lens, develop cataract. Estrogen will be administered to these animals to determine if it can prevent or lessen the severity of the cataract. 2.4 Influence of produced on expression of TGFB receptors. Produced rats with and without estrogen replacement will be used to study the expression of TGFB receptors by immunohistochemistry and in situ hybridization.